Crystalline freebase forms of a biphenyl compound
The invention provides two crystalline freebase forms of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. The invention also provides pharmaceutical compositions comprising the crystalline freebase or prepared using the crystalline freebases; processes and intermediates for preparing the crystalline freebases; and methods of using the crystalline freebases to treat a pulmonary disorder.
1. A method for preparing a pharmaceutical composition for use in a nebulizer inhaler, the method comprising dissolving a crystalline freebase of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester in an aqueous pharmaceutical carrier to form an aqueous solution; wherein the crystalline freebase is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.6±0.1, 13.1±0.1, 18.6±0.1, 19.7±0.1, and 20.2±0.1.
2. The method of claim 1 , wherein the crystalline freebase is further characterized by five or more additional diffraction peaks at 2θ values selected from 8.8±0.1, 10.1±0.1, 11.4±0.1, 11.6±0.1, 14.8±0.1, 15.2±0.1, 16.1±0.1, 16.4±0.1, 16.9±0.1, 17.5±0.1, 18.2±0.1, 19.3±0.1, 19.9±0.1, 20.8±0.1, 21.1±0.1, 21.7±0.1, and 22.3±0.1.
3. The method of claim 1 , wherein the crystalline freebase is further characterized by a powder x-ray diffraction pattern having peak positions in accordance with the peak positions shown in FIG. 1 .
4. The method of claim 1 , wherein the crystalline freebase is further characterized by a melting point of about 125° C.
5. The method of claim 1 , wherein the crystalline freebase is further characterized by a differential scanning calorimetry thermogram in accordance with that shown in FIG. 4 .
6. The method of any one of claims 1 to 5 , wherein the aqueous solution is isotonic.
7. The method of any one of claims 1 to 5 , wherein the aqueous solution has a pH of about 4-6.
8. The method of any one of claims 1 to 5 , wherein the aqueous solution is buffered with citrate buffer to a pH of about 5.
9. The method of any one of claims 1 to 5 , wherein the aqueous solution contains about 0.05 μg/mL to about 10 mg/mL of biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}-ethyl)piperidin-4-yl ester.